The role of Foxp1/2/4 mediated chromatin remodeling in skin and hair follicle dev

Foxp1/2/4 介导的染色质重塑在皮肤和毛囊发育中的作用

• 批准号: 7678121
• 负责人: EDWARD E MORRISEY
• 金额: $ 6.86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678121
• 关键词: Adult; Affect; Basal Cell; Cardiovascular system; Cell Differentiation process; Cell Lineage; Cell physiology; Chromatin Remodeling Factor; DBL Oncoprotein; DNA Binding; DNA Sequence; Data; Defect; Development; Disease; Epigenetic Process; Event; Failure; Foxes; Gene Family; Gene Targeting; Genes; Genetic Transcription; HDAC1 gene; HDAC2 gene; Hair; Hair follicle structure; Heart; Histone Deacetylase; Homeostasis; Knock-out; Knockout Mice; Lead; Lung; Mediating; Molecular; Mus; Mutant Strains Mice; NuRD complex; Pathway interactions; Pattern; Play; Pluripotent Stem Cells; Population; Regulation; Repression; Role; Skin; Skin Cancer; Stem cells; System; Tissues; base; cell type; chromatin remodeling; embryonic stem cell; gene repression; in vivo; loss of function; lung development; member; novel; recombinase; research study; self-renewal; skin lesion; stem; stem cell population; transcription factor

Recent evidence has shown that alterations in epigenetic states can alter the ability of stem cell populations to differentiate into specific cell lineages and in some circumstances lead to the de-differentiation of differentiated cell types into more pluripotent stem cells. The molecular pathways controlling such epigenetic/chromatin remodeling events are still unclear. The forkhead or Fox gene family of transcriptional regulatory factors regulate tissue specific gene transcription and are important for self-renewal and differentiation of stem/progenitor cell populations during development. We have shown that the Foxp1/2/4 subfamily of Fox factors are highly expressed in developing skin and hair follicles. Recent evidence from our lab as well as others demonstrated that Foxp1/2/4 and the related FoxpS factor interact with chromatin remodeling complexes, including NuRD and NCoR to repress gene specific expression during cell differentiation. Evidence from our lab shows that Foxp1/2/4 interact with components of the NuRD complex, mediating transcriptional repression of important target genes in the lung and heart. Our preliminary data suggest that Foxp1/2/4-NuRD interactions have profound affects on lung development as demonstrated by defects in Foxp1-HDAC2 and Foxp2-HDAC2 compound mutant mice. These studies illustrate one of the few examples of the chromatin remodeling complex NuRD interacting with a sequence specific DNA binding transcription factor. Given these fundamental roles for Foxp1/2/4 in development of the cardiovascular and pulmonary systems, we predict that they will play a similarly critical role in regulation of hair follicle development. To explore the role of Foxp1/2/4 in skin and hair follicle development, we propose to 1) determine the roles for Foxp1/2/4 in skin and hair follicle development by deleting these genes in epidermal specific knockout mice and 2) Determine the roles for HDAC1/2 in skin and hair follicle development through in vivo loss of function analyses.

最近的证据表明，表观遗传状态的改变可以改变干细胞群体的能力， 以分化成特定的细胞谱系，并且在某些情况下导致细胞的去分化， 将细胞类型分化为更多的多能干细胞。控制这些的分子途径 表观遗传/染色质重塑事件仍不清楚。转录调控的叉头或Fox基因家族 调节因子调节组织特异性基因转录，对自我更新和 干/祖细胞群在发育过程中的分化。我们已经证明，Foxp 1/2/4 Fox因子的亚家族在发育中的皮肤和毛囊中高度表达。我们最近的证据显示， 实验室和其他人证明Foxp 1/2/4和相关的FoxpS因子与染色质相互作用 重塑复合物，包括NuRD和NCoR，以抑制细胞周期中的基因特异性表达， 分化来自我们实验室的证据表明Foxp 1/2/4与NuRD复合物的组分相互作用， 介导肺和心脏中重要靶基因的转录抑制。我们的初步数据 提示Foxp 1/2/4-NuRD相互作用对肺发育具有深远影响， Foxp 1-HDAC 2和Foxp 2-HDAC 2复合突变小鼠中的缺陷。这些研究说明了为数不多的 染色质重塑复合物NuRD与序列特异性DNA结合相互作用的例子 转录因子考虑到Foxp 1/2/4在心血管疾病发展中的这些基本作用， 肺系统，我们预测，他们将发挥同样重要的作用，在调节毛囊 发展为了探索Foxp 1/2/4在皮肤和毛囊发育中的作用，我们建议：1） 通过删除表皮细胞中的Foxp 1/2/4基因，确定Foxp 1/2/4在皮肤和毛囊发育中的作用。 特异性基因敲除小鼠和2）确定HDAC 1/2在皮肤和毛囊发育中的作用， 体内功能丧失分析。